Hemodialysis, hereinafter referred to as kidney dialysis, or simply “dialysis, is a medical procedure that is performed on human patients (and also on a smaller scale, pet animals), to remove toxins from the blood in a similar manner to a functioning kidney. When a person or animal's kidneys cease to function properly due to one or more of a number of acute or chronic diseases or conditions (diabetes is a known causative factor in renal failure), toxins accumulate in the bloodstream.
Failure to remove these toxic compounds—primarily urea, uric acid and its analogues, and other nitrogenous compounds such as creatinine; and excess amounts of elements such as potassium, phosphorous, sodium, chloride and other minerals—from the blood results in deterioration of body tissues and organ systems, eventually resulting in death.
Dialysis may be performed in a hospital setting or clinic; or in some cases, the patient is trained to perform the procedure at home on an outpatient basis. Two primary types of dialysis are regularly performed—conventional hemodialysis and peritoneal dialysis. In conventional dialysis, the patient is connected (via an arteriovenous fistula, graft or by catheter) to a dialysis machine. The dialysis machine functions to pump the contaminated blood from the patient through a dialyzer, where the blood is filtered through a dialyzing solution, and thence returned to the patient. Conventional hemodialysis usually takes between 3-6 hours and is normally performed at a clinic or hospital several times per week.
In peritoneal dialysis, a catheter is inserted into the patient's abdomen, with the catheter connected its other end to a supply of dialysis solution. In a typical peritoneal dialysis exchange, dialysis solution is introduced into the patient's abdominal cavity through the catheter and allowed to remain there for a predetermined time period (called a “dwell”). During the period when the peritoneal cavity is filled with the solution, waste products and excess body fluids pass through the peritoneum, where they encounter the dialysis solution and are removed from the body when the solution is later drained from the body. The draining/filling process (the “cycle”) is normally repeated several times daily, with a long dwell overnight. Periodic testing is performed to determine the efficacy of the dialysis.
Typical dialysis solution is a dextrose-based solution, with the solution also including a quantity of salt and other dissolved minerals, and perhaps electrolytes as determined by the needs of each patient. The dialysis solution functions to increase osmotic pressure in the peritoneal cavity to cause maximum diffusion of excess fluids and waste products from the blood. The dialysis solution also serves to bind waste products for removal during the draining process, and to deliver necessary minerals and electrolytes to the body (many renal failure patients are placed on diets that shortchange necessary minerals, and must be ingested separately).
Mesna (sodium 2-mercaptoethene sulfonate) and dimesna (disodium 2,2′-dithiobis ethane sulfonate) are known therapeutic compounds that have heretofore demonstrated a wide variety of therapeutic uses. Both mesna and dimesna have been shown to be effective protective agents against certain specific types of toxicity associated with the administration of cytotoxic drugs used to treat patients for various types of cancer.
In particular, mesna has been used with some success in mitigating the toxic effects of cytotoxic agents such as ifosfamide, oxazaphosphorine, melphalane, cyclophosphamide, trofosfamide, sulfosfamide, chlorambucil, busulfan, triethylene thiophosphamide, triaziquone, and others, as disclosed in U.S. Pat. No. 4,220,660, issued Sep. 2, 1980.
The near absence of toxicity of dimesna further underscores the usefulness of this compound, as large doses can be given to a patient without increasing the risk of adverse effects from the protective agent itself.
Further, pharmacological profiles of each compound indicate that, if proper conditions are maintained, mesna and dimesna do not prematurely inactivate primary therapeutic drugs to a significant degree. Thus, neither compound will significantly reduce activity of the chemotherapeutic agent, and in many cases, act to potentiate the effect of the main drug on targeted cancer cells.
The molecular structures of both mesna and dimesna are shown below as Structure I and Structure II respectively.HS—CH2—CH2—SO3Na  (I)NaSO3—CH2—CH2—S—S—CH2—CH2—SO3Na  (II)
As shown, dimesna is a dimer of mesna, with the optimum conditions for oxidation occurring in the slightly basic (pH ˜7.3), oxygen rich environment found in blood plasma. In mildly acidic, low oxygen conditions, in the presence of a reducing agent such as glutathione reductase, conditions prevalent in the kidneys, the primary constituent is mesna.
Mesna acts as a protective agent for a number of cytotoxic agents by substituting a nontoxic sulfhydryl moiety for a toxic hydroxy (or aquo) moiety. This action is particularly evidenced in the coadministration of mesna and oxazaphosphorine, and in the administration of dimesna along with certain platinum agents and/or taxanes.
Dimesna, as well as some analogues, have excellent toxicity profiles in mammalian species. In fact, dimesna has been administered intravenously to mice and dogs in doses higher than the accepted oral LD50 for common table salt (3750 mg/kg), with no adverse effects. Dimesna has also been administered to humans in doses exceeding 40 g/m2, with no adverse effects.
Mesna, and other analogues with free thiol moieties, constitute the more physiologically active form of the two types of compounds described in this specification. These compounds manifest their activity by providing free thiol moieties for terminal substitution at locations where a terminal leaving group of appropriate configuration, usually a hydroxy, aquo or superoxide is located. Mesna also tends to form conjugates with naturally occurring biochemicals that contain a free thiol moiety, such as cysteine, glutathione, homocysteine, and others.
Dimesna and other disulfides can be activated intracellularly by glutathione reductase, a ubiquitous enzyme, thereby generating high concentrations of intracellular free thiols. These free thiols act to scavenge the free radicals and other nucleophilic compounds often responsible for causing cell damage.
This profile is especially significant in explaining the success of dimesna in controlling and mitigating the toxic effects of platinum complex antitumor drugs. The mechanism for action in the case of cisplatin (cis-diammine dichloro platinum) is explained in U.S. Pat. No. 5,789,000, which is incorporated herein by reference.
Mesna, dimesna, and analogues of these compounds have been the subject of several prior pharmaceutical uses described in the literature and in prior patents, both in the United States and around the world. In addition to the cytotoxic agent protection uses, one or more of these compounds have proven effective, in vitro, against a multiplicity of biological targets, and have been effective, in vivo, in the treatment of sickle cell disease, radiation exposure, chemical agent exposure, and other uses.
Mesna, dimesna, and analogues thereof are synthesized from commonly available starting materials, using acceptable routes well known in the art. One such method involves the two-step, single pot synthetic process for making dimesna and like compounds of the following formula:R1—S—R2;wherein:                R1 is hydrogen, X-lower alkyl, or X-lower alkyl-R3;        R2 is -lower alkyl-R4;        R3 and R4 are each individually SO3M or PO3M2;        X is absent or X is sulfur; and        M is an alkali metal.        
The process essentially involves a two-step single pot synthetic process, which results in the conversion of an alkenyl sulfonate salt or acid to the desired formula I compound. The process in the case of mesna is a single step process that converts the alkenyl sulfonate salt to mesna or a mesna derivative by reacting with an alkali metal sulfide or with hydrogen sulfide.
If the desired end product is dimesna or a dimesna analogue, a two-step single pot process is involved. Step 1 is as described above. Step 2 of the process is performed in the same reaction vessel as Step 1 without the need to purify or isolate the mesna formed during that step. Step 2 includes the introduction of oxygen gas into the vessel, along with an increase in pressure and temperature above ambient values, at least 20 pounds per square inch (psi) and at least 60° C. Dimesna or a derivative thereof is formed in essentially quantitative yield.
Other processes, well known and documented in the prior art, may be employed to make either mesna or dimesna, or derivatives and analogues thereof.